tbuckley/cabot-search huggingface dataset:
Abstract 2416: Uncovering the protective neurological mechanisms of hypofractionated FLASH radiotherapy
Authors: Charles L. Limoli, Barrett D. Allen, Eniko A. Kramár, Yasaman Alaghband, Marie-Catherine Vozenin
Journal: Cancer Research (2023)

Abstract Implementation of ultra-high dose-rate FLASH radiotherapy (FLASH-RT) is rapidly gaining traction as a unique cancer treatment modality able to dramatically minimize normal tissue toxicity while maintaining anti-tumor efficacy compared to standard of care radiotherapy at conventional dose rate (CONV-RT). The resultant improvements in the therapeutic index have sparked intense investigations in pursuit of the underlying mechanisms. As a preamble to clinical translation, we exposed non-tumor bearing male and female mice to hypofractionated (3x10 Gy) whole brain FLASH- and CONV-RT to evaluate differential neurological responses using a comprehensive panel of functional and molecular outcomes over a 6-month follow up. In each instance, extensive and rigorous behavioral testing showed FLASH-RT to preserve cognitive indices of learning and memory that corresponded to a similar protection of synaptic plasticity as measured by long-term potentiation (LTP). These beneficial functional outcomes were not found after CONV-RT and were linked to a preservation of synaptic integrity at the molecular (synaptophysin) level and to reductions in neuroinflammation (CD68+ microglia) throughout specific brain regions known to be engaged by our selected cognitive tasks (hippocampus, medial prefrontal cortex). Ultra-structural changes in pre/post-synaptic bouton (Bassoon/Homer-1 puncta) within these same regions of the brain were not found to differ in response to dose rate. With this clinically relevant dosing regimen, we provide a mechanistic blueprint from synapse to cognition detailing how FLASH-RT reduces normal tissue complications in the irradiated brain. Citation Format: Charles L. Limoli, Barrett D. Allen, Eniko A. Kramár, Yasaman Alaghband, Marie-Catherine Vozenin. Uncovering the protective neurological mechanisms of hypofractionated FLASH radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2416.
Abstract 3737: A novel mechanism of NF-κB activation by genotoxic chemotherapy
Authors: Jaganathan Venkatesh, Magesh Muthu, Arun K. Rishi
Journal: Cancer Research (2023)

Abstract CARP-1, a perinuclear phospho-protein, is a biphasic regulator of cell survival and apoptosis signaling. Genotoxic drugs induce apoptosis in part by elevating CARP-1 levels while also promote cell survival in part by activating NF-κB that involves CARP-1 interaction with NF-κB kinase subunit γ (aka, NEMO). We previously noted interaction of CARP-1 with RIPK1, and since RIPK1 is known to regulate NF-κB signaling, we investigated whether RIPK1-CARP-1 interaction is involved in genotoxic chemotherapy-dependent apoptosis or NF-κB-activated survival signaling. Mutagenesis and co-IP-WB analyses revealed that a 40-amino acid epitope within the amino-terminal catalytic domain of RIPK1 interacted with CARP-1 (611-640) peptide. Overexpression of this CARP-1/CCAR1-binding (CB) epitope peptide or RIPK1 mutant that has in-frame deletion of CB-epitope resulted in moderate but significant reduction in viabilities of cells treated with Adriamycin or Cisplatin relative to the viability loss noted in cells expressing RIPK1 (WT). However, no significant differences in loss of cell viabilities were noted in cells expressing various substitution mutants of RIPK1 (aspartate (D) 138 to asparagine (N), serine (S) 109 and threonine (T) 110 to alanines (A), lysine (K) 87 to arginine (R), K97 to R, K105 to R, or K115 to R) relative to their RIPK1 (WT) expressing counterparts when treated with genotoxic drugs. Interestingly, CB-epitope mutant, but not RIPK1 (WT), failed to translocate to cytoplasm in Adriamycin-treated cells. Genotoxic drugs activated p65/RelA in cells expressing RIPK1 (WT), while expression of RIPK1 CB-epitope mutant resulted in abrogation of p65/RelA activation by Adriamycin or Cisplatin but not by TNFα. Collectively our data demonstrate that CARP-1 interaction with RIPK1 promotes nuclear export of RIPK1 and consequent NF-κB activation in cells exposed to genotoxic drugs. Citation Format: Jaganathan Venkatesh, Magesh Muthu, Arun K. Rishi. A novel mechanism of NF-κB activation by genotoxic chemotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3737.
Abstract 2264: Role of first-line immune checkpoint inhibitors monotherapy for oncogene-driven non-small cell lung cancer
Authors: Ying-Yin Chen, Chen-Wen Lin, Yenh-Chen Hsein, Chung-Yu Chen
Journal: Cancer Research (2023)

Abstract Though improvement of overall survival in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) was observed, their efficacy varies greatly among different immune and molecular profiles in tumors. Particularly, the clinical significance of ICIs for oncogene-driven NSCLC has been controversial. In this study, after excluding NSCLC patients harboring driven oncogenes as EGFR, ALK and ROS1 mutation, twenty NSCLC patents with higher Programmed cell death 1 ligand 1 (PD-L1) expression (PD-L1 ≧ 50%, immunohistochemical stained by SP263 or 22C3) were administered with Pembrolizumab alone as first-line immunotherapy. NSCLC patients with more higher PDL1 expression (PD-L1 ≧ 80%) had longer progression-free survival (PFS) PD-L1 ≧ 80% v.s. PD-L1 &amp;lt; 80%, PFS, median, 11.2 v.s 7.0 months, hazard ratio [HR]: 0.52, p = 0.03). 10 of them had other driven oncogenes (5 for KRAS, 3 for MET, 1 for BRAF and 1 for NRAS) were detected by next-generation sequencing (NGS) (Illumina iSeq 100 Sequencing System; AmpliSeq for Illumina Focus Panel). Patients harboring driven oncogene had shorter PFS by first-line immunotherapy as Pembrolizumab (With driven oncogene v.s. without, PFS, median, 4.2 v.s.10.8 months, HR: 2.76, p = 0.001). In conclusion, NGS analysis was recommended even the NSCLC patients with higher PD-L1 expression before immunnotherapy. First-line ICIs monotherapy should be cautious for oncogene-driven NSCLC patients. Citation Format: Ying-Yin Chen, Chen-Wen Lin, Yenh-Chen Hsein, Chung-Yu Chen. Role of first-line immune checkpoint inhibitors monotherapy for oncogene-driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2264.
Abstract 4821: Exploring the role of a solid-like condensate in breast and prostate cancer
Authors: Alexander Grunfeld, Michael Bokros, Chloe Kirk, Stephen Lee
Journal: Cancer Research (2023)

Abstract Cancer cells are exposed to harsh environmental conditions, which they adapt to by engaging various stress response pathways. A common cellular response to these stressors is the assembly of membraneless compartments known as biomolecular condensates. Our lab discovered one such pathway where exposure to environmental stressors reversibly converts nucleoli into solid-like condensates known as Amyloid bodies (A-bodies). A-bodies induce a state of cellular dormancy by sequestering in an amyloid-like state key proteins involved in processes such as DNA replication and cell cycle progression. In vitro experiments showed that suppressing A-body formation in cancer cell lines accelerates tumorigenesis, suggesting that system-wide amyloidogenesis is a mechanism of tumor suppression. The goal of this project was to investigate how A-bodies correlate with tumorigenesis in the context of human tissues. Using formalin-fixed paraffin embedded (FFPE) sections of breast invasive ductal carcinoma and prostate adenocarcinoma, we first confirmed the presence of A-bodies in tumors by staining with the amyloidophilic dye Amylo-glo. In agreement with in vitro data in breast and prostate cancer cell lines, immunohistochemical staining further showed these condensates contain known A-body constituent proteins. Co-staining tissues with Amylo-glo and the proliferation marker Ki67 revealed a negative correlation between A-bodies and cell proliferation, supporting the hypothesis that A-bodies suppress cell growth. Finally, tissue staining comparing primary tumors with distant metastases suggests that A-body biogenesis is reduced in the progression to metastatic disease. Together, our preliminary data presents a biomolecular condensate which can be visualized in human tissues and inversely correlates with cell proliferation. Future directions include examining additional tumor types for the presence of A-bodies and testing the correlation between A-bodies and other markers of proliferation, cell cycle arrest, and environmental stress. Citation Format: Alexander Grunfeld, Michael Bokros, Chloe Kirk, Stephen Lee. Exploring the role of a solid-like condensate in breast and prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4821.
Abstract 2617: Rac and Cdc42 inhibition on macrophage function in the pancreatic tumor microenvironment
Authors: Anamaris Torres-Sánchez, Michael Rivera-Robles, Stephanie Dorta-Estremera, Suranganie Dharmawardhane
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. To date, there are few therapies that are efficient against this disease, and patients often develop therapy resistance. The homologous Rho GTPases, Rac and Cdc42, are overexpressed in pancreatic cancer and correlated with poor prognosis. Rho GTPases regulate cell migration/invasion, cell morphology/polarity, and cell survival/viability. Rac and Cdc42 are essential Rho GTPases in oncogenic transformation and invasiveness and govern invasion in both cancer cells and tumor-associated macrophages (TAMs). TAMs are immunosuppressive cells that exacerbate cancer progression via inflammatory responses and crosstalk signaling with malignant cancer cells to promote invasion and immunesuppression. Our laboratory has developed a dual Rac/Cdc42 inhibitor, MBQ-167 (IC50 100nM), as an anticancer agent that recently received IND approval from the US FDA due to its safety and efficacy in breast cancer models. The hypothesis tested in this study is that MBQ-167 will simultaneously target the migration and activity of pancreatic cancer cells and immunosuppressive cells in the tumor microenvironment (TME). To evaluate this, we performed pulldown assays for Rac and Cdc42 activation, MTT cell viability assays, wound-healing assays for cell migration, and phagocytosis assays using human and rat macrophage and human pancreatic cancer cell lines. Results show that MBQ-167 is not toxic to macrophages even at concentrations as high as 10uM. MBQ-167 inhibited Rac1activation by 75% and Cdc42 activation by 40% in THP-1 human macrophages at 500nM. MBQ-167 reduced macrophage migration by 67% at 150nM, and decreased pancreatic cancer cell migration by 60% at 250nM. In addition, MBQ-167 reduced macrophage phagocytosis by 56% at 500nM. This study demonstrates the utility of Rac/Cdc42 inhibition to reduce pancreatic cancer progression in the TME. Citation Format: Anamaris Torres-Sánchez, Michael Rivera-Robles, Stephanie Dorta-Estremera, Suranganie Dharmawardhane. Rac and Cdc42 inhibition on macrophage function in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2617.
Abstract 4401: The precision chemotherapy to improve the epithelial ovarian cancer prognosis
Authors: Seongeun Pak, Youn Jin Choi
Journal: Cancer Research (2023)

Abstract Purpose: Recurrence is common in ovarian cancer patients, even in those patients who show complete response after first-line chemotherapy, 80% of the patients experience a recurrence. So gynecologic oncologists often have to consider several factors when choosing next chemotherapy regimen. Therefore, this study aimed to find serial chemotherapy regimen choice to anticipate patients’ better prognosis. Materials and Methods: We reviewed 656 patients diagnosed ovary cancer in one tertiary institutional hospital between 2006 and 2020. Patents’ clinic-pathologic characteristics, primary treatment, chemotherapy regimens, survival outcomes were collected. We divided patients into several groups according to their chemotherapy regimen by mechanism of action and compared them. 1st line chemotherapy(CTx) type 1: carboplatin-paclitaxel, carboplatin-docetaxol, cisplatin-paclitaxel, cisplatin-docetaxol2nd line CTx type 1: carboplatin-paclitaxel, carboplatin-docetaxol, cisplatin-paclitaxel, cisplatin-docetaxol2nd line CTx type 4: carboplatin-gemcitabine2nd maintenance CTx type 2: PARP inhibitor(PARPi)2nd line CTx Type 5: Platinum + topoisomerase inhibitor 2nd line CTx Type 6(cisplatin-vinorelbine)2nd line CTx Type 8(topoisomerase inhibitor only) 2nd line CTx Type12 (single taxol) The survival rate of ovary cancer patients decreased from stage 1 to stage 4.Among 1st line CTx type 1 and 2nd line CTx type(1 or 4) patients, those who used PARPi in 2nd line maintenance CTx(n=14) had a higher death rate than those who did not receive maintenance CTx or received that other than PARPi(hazard ratio 1.44). In the 1st line CTx 1~4 group, we divided patients according to 2nd line CTx type. We compare 2nd line CTx type 5 group(n=30) with type 6+8+12 group(n=26). The death rate was of type 5 group was higher than type 6+8+12 group. And Overall survival of 2nd line CTx type 5 group was 22 months, that of 2nd line CTx type 6+8+12 group was 26 months. Conclusion: When changing the chemotherapy regimen in the recurrence of ovarian cancer, the survival rate or overall survival may vary depending on the order in which the regimen is used. If we collect patients data more broadly, the predictive power will be better. Citation Format: Seongeun Pak, Youn Jin Choi. The precision chemotherapy to improve the epithelial ovarian cancer prognosis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4401.
Abstract 3969: Screening of kinase inhibitors as bioenergetic metabolism modulator using the XF Real-Time ATP Rate Assay
Authors: Yoonseok Kam, Lisa Winer, Natalia Romero
Journal: Cancer Research (2023)

Abstract Cancer cells are metabolically reprogrammed through tumor initiation and progression, and there are increasing developments in cancer therapies exploiting the potential metabolic vulnerability. A better understanding of cancer cell metabolic regulation can also contribute to modulating the harsh tumor microenvironment, which strongly affects the efficacy of emerging anti-cancer immunotherapies. As one of the critical contributors to cancer therapy design, there is increasing demand for time-efficient and reliable analytic tools when searching for drugs and genes modulating cancer cell metabolism. The XF Real-Time ATP Rate Assay measures ATP production from glycolysis and mitochondrial respiration simultaneously and provides a quantitative overview of the bioenergetic phenotype of the cells. By using ATP production rate as a universal unit of bioenergetic metabolism, this assay quickly detects metabolic modulations induced by chemical stimuli or genetic modifications. It allows the identification of potential targets for therapy design. In this study, we used the Seahorse XF Pro Analyzer combined with the XF ATP Rate assay to screen 80 kinase inhibitors for the suppressive effects on energy metabolism and/or inducing a metabolic phenotype shift in THP-1 cells, a monocytic leukemia cell line, using PBMC as the control. We identified four mitochondrial and two glycolytic suppressors using the screening and dose-response views available in Seahorse Analytics, a cloud-based data analysis tool for Seahorse XF assays. These compounds showed moderate or no effects on the net ATP production rates but induced a significant shift in the metabolic phenotype of THP-1 cells. Among the selected kinase inhibitors, AG-879 (ErbB2 inhibitor), SU-1498 (VEGFR inhibitor), and U-0126 (MEK1/2 inhibitor) showed the most potent inhibitory effect on mitochondrial energy production in THP-1 cells. Dose-response studies indicated that SU-1498 and U-0126 have higher potency in THP-1 than PBMC, and thus they can be considered good cancer-cell targets for mitochondrial suppressors. In contrast, AG-879 showed a similar or higher inhibitory effect on PBMC even though it is the most potent mitochondrial suppressor among the selected compounds. These results demonstrate that the XF Real-Time ATP Rate Assay can be used as a primary assay for screening and validating drug candidate(s) targeting the bioenergetic metabolism of cancer cells. Citation Format: Yoonseok Kam, Lisa Winer, Natalia Romero. Screening of kinase inhibitors as bioenergetic metabolism modulator using the XF Real-Time ATP Rate Assay. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3969.
Abstract 391: Adenylosuccinate lyase enzyme is essential for growth of endocrine therapy resistant ER+ breast cancer cells
Authors: Anil K. Yadav, Robert Clarke, Surojeet Sengupta
Journal: Cancer Research (2023)

Abstract The endocrine therapy (ET) that targets estrogen synthesis (aromatase inhibitors) or estrogen receptor mediated signaling (tamoxifen, or Fulvestrant) is the mainstay therapy for estrogen-receptor positive (ER+) breast cancer. However, emergence of resistance to ET is a major clinical challenge as it leads to relapse and disease progression that cannot be further treated with any targeted therapy. We studied the role of a key enzyme involved in de-novo purine biosynthesis, adenylosuccinate lyase (ADSL), in the growth and proliferation of ER+, ET-resistant breast cancer cells. ADSL enzyme is responsible for the catalysis of two non-sequential steps in de-novo purine synthesis pathway that produces aminoimidazole carboxamide ribonucleotide (AICAR) and adenosine monophosphate (AMP) as well as generates fumarate as a byproduct. Here we show that siRNA mediated depletion of ADSL in two different ER+, ET-resistant cell lines, namely LCC9 and T47D-4HT cells, block the proliferation of the cells in 2-D cell culture as well as in spheroid formation. Our investigation revealed that reduced growth of cells after ADSL-depletion was due to cell-cycle perturbation in both LCC9 and T47D-4HT cells and not cell death. Intriguingly, the cell cycle was blocked at different phases in LCC9 and T47D-4HT cells. After ADSL knock-down the LCC9 cells were arrested at G1/S boundary with concurrent elevated levels of cyclin D1 protein whereas the T47D-4HT cells were blocked at S/G2-M boundary with reduced levels of cyclin D1. In addition, we observed that ADSL deficient cells had low levels of ATP in conjunction with attenuated mitochondrial membrane potential. Notably, addition of low concentration of AICAR (but not AMP, adenosine, or fumarate) to ADSL deficient LCC9 cells partially rescue reduced proliferation of cells as well as restored the mitochondrial membrane potential. Our data establishes that ADSL enzyme function is critical for proliferation of ET-resistant ER+ breast cancer cells and its deficiency impair the mitochondrial function and energy production. We propose that ADSL is a potentially novel therapeutic target for ER+, endocrine therapy resistant breast cancer. Citation Format: Anil K. Yadav, Robert Clarke, Surojeet Sengupta. Adenylosuccinate lyase enzyme is essential for growth of endocrine therapy resistant ER+ breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 391.
Abstract 673: p38γ MAPK remodels tumor microenvironment facilitating breast cancer progression and brain metastasis
Authors: Xiangliang Yuan, Hao-Nien Chen, Akosua Badu-Nkansah, Yimin Duan, Dihua Yu
Journal: Cancer Research (2023)

Abstract Major neoplastic diseases have high incidences of brain metastasis (BrM) which is a clinically dreadful consequence of advanced cancers with an abysmal prognosis. Unfortunately, our understanding of the biology and molecular mechanisms underlying BrM remains rudimentary. Improving our understanding of the pathogenesis of BrM will facilitate the rational development and prioritization of new therapeutic strategies. Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine protein kinases that are key players in various intracellular signaling pathways controlling many cellular processes, e.g., growth, differentiation, stress responses, and immune defense which have a key role in cancer progression. However, little is known regarding the role of MAPKs in the pathogenesis of BrM. Here, we report that p38γ mitogen-activated protein kinase (MAPK12) is overexpressed in multiple tumor types and associated with aggressive breast cancer progression and a poor outcome in BrM patients. Interestingly, we found that the lack of p38γ did not impact the proliferation of tumor cells ex vivo, but significantly reduced both the primary tumor growth and BrM in EO771 and other mammary tumor-bearing immunocompetent mouse models. Our preclinical data indicated that p38γ promoted tumor progression and BrM through remodeling tumor microenvironments in vivo. We have mapped the immune landscape of BrM lesions of EO771-bearing mice using high-dimensional single-cell profiling. Clearly, cytometry by time-of-flight (CyTOF) analysis of the BrM immune infiltrates revealed reprogramming of the immunosuppressive brain microenvironment toward a proinflammatory and antitumoral state with tumor-intrinsic p38γ depletion, as indicated by highly enriched dendritic cell (DC) and cytolytic T cell (CTL) populations in BrM. To explore the impact of p38γ depletion in breast cancer cells, we performed RNA sequencing on EO771 cells having p38γ knocked down versus the control cells. We found that p38γ knocked down led to the upregulation of pathways related to immune cell movement, thereby leading to an increased accumulation of antitumor immune cells in BrM. Together, our findings uncover an important role for tumor-intrinsic p38γ in shaping the brain immune microenvironment and underscore the potential of specific p38γ blockade in enhancing antitumor immunity for the treatment of breast cancer BrM. Citation Format: Xiangliang Yuan, Hao-Nien Chen, Akosua Badu-Nkansah, Yimin Duan, Dihua Yu. p38γ MAPK remodels tumor microenvironment facilitating breast cancer progression and brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 673.